A cross-sectional study of the association between heavy metals and pan-cancers associated with sex hormones in NHANES 1999-2018.

Given the complexity of tumorigenesis, numerous studies have also shown that excessive exposure to heavy metals increases the risk of cancers and disrupts the secretion of sex hormones. However, the specific effects of heavy metals on cancers remain to be proven. To confirm the association between heavy metals and pan-cancer sex hormone levels among adults, 94,337 individuals from the National Health and Nutrition Examination Survey were assessed. We examined the associations between pan-cancers associated with sex hormones (ovarian, testicular, breast, and prostate cancers) and heavy metals in blood/urine. The methods (the WQS (weighted quantile sums) and SVYGLM (survey generalized linear model) regressions) were used to evaluate the association between sex hormone-related cancers and each metal category by incorporating covariates. To evaluate the overall effect of heavy metals and detect the dose-response relationship between the prevalence of pan-cancers associated with sex hormones and heavy metals, RCS (restricted cubic splines) were applied. Environmental exposure to heavy metals may be associated with pan-cancers associated with sex hormones in adults in the USA. Prostate cancer was inversely associated with blood cadmium while positively associated with blood lead, urinary tin, and thallium. Breast cancer was inversely associated with blood lead. Ovarian cancer was positively associated with blood cadmium. We also found a non-linear dose-response relationship between pan-cancers associated with sex hormones and heavy metals, which was non-parametric, using RCS models. The OR for breast cancer decreased along with the increase in lead concentration under approximately 20 µg/dl, while the OR for prostate cancer increased between urine thallium levels of approximately 0.17-1.1 ng/ml. Pan-cancers associated with sex hormones are associated with exposure to heavy metals. Considering the design of the NHANES study, further studies need to be conducted on other nationally representative surveys.

Reconstruction of complex chest wall defects: A case report.

BACKGROUND: Chronic radiative chest wall ulcers are common in patients undergoing radiation therapy. If not treated early, then symptoms such as erosion, bleeding and infection will appear on the skin. In severe cases, ulcers invade the ribs and pleura, presenting a mortality risk. Small ulcers can be repaired with pedicle flaps. Because radioactive ulcers often invade the thorax, surgeons need to remove large areas of skin and muscle, and sometimes ribs. Repairing large chest wall defects are a challenge for surgeons. CASE SUMMARY: A 74-year-old female patient was admitted to our department with chest wall skin ulceration after radiation therapy for left breast cancer. The patient was diagnosed with chronic radioactive ulceration. After multidisciplinary discussion, the authors performed expansive resection of the chest wall ulcers and repaired large chest wall defects using a deep inferior epigastric perforator (DIEP) flap combined with a high-density polyethylene (HDPE) patch. The patient was followed-up 6 mo after the operation. No pigmentation or edema was found in the flap. CONCLUSION: DIEP flap plus HDPE patch is one of the better treatments for radiation-induced chest wall ulcers.

Aging alters Hv1-mediated microglial polarization and enhances neuroinflammation after peripheral surgery.

Perioperative neurocognitive disorders have been widely recognized as common adverse events after surgical intervention. Aging is one of the most important independent risk factors for worsened cognitive outcome, and this deterioration is linked to exacerbated microglia-mediated neuroinflammation in the aged brain. Under pathological stimulation, microglia are capable of polarizing toward proinflammatory M1 and anti-inflammatory M2 phenotypes. In the present study, we examined how aging affects microglial responses and neuroinflammation following peripheral surgery. Adult (2-3 months) and aged (18 months old) male C57/BL6 mice were subjected to tibial fracture or sham surgery. Aged mice exhibited higher level of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) in the hippocampus. The expression of synaptic protein synaptophysin (SYP) was also markedly reduced in the aged brain after the surgery. Both adult and aged mice showed significant increases in M1 microglial polarization (CD16/32). In contrast, tibial fracture surgery induced a decreased M2 microglial polarization (CD206, Ym1/2, Arg1) in aged brain but enhanced M2 microglial polarization in adult brain. Aged mice have upregulated voltage-gated proton channel (Hv1) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit expression compared with adult mice. The percentage of CD16/32-positive M1 microglia colabeling with Hv1 was higher in aged mice after tibial fracture surgery. Thus, Hv1/NADPH oxidase upregulation in the aged brain may shift the dynamic equilibrium of microglial activation toward M1 polarization and exaggerate postoperative neuroinflammatory responses after peripheral surgical intervention.

Cell cycle activation contributes to isoflurane-induced neurotoxicity in the developing brain and the protective effect of CR8.

AIMS: It is well established that exposure of common anesthetic isoflurane in early life can induce neuronal apoptosis and long-lasting cognitive deficit, but the underlying mechanisms were not well understood. The cell cycle protein Cyclin B1 plays an important role in the survival of postmitotic neurons. In the present study, we investigated whether cyclin B1-mediated cell cycle activation pathway is a contributing factor in developmental isoflurane neurotoxicity. METHODS: Postnatal day 7 mice were exposed to 1.2% isoflurane for 6 hours. CR8 (a selective inhibitor of cyclin-dependent kinases) was applied before isoflurane treatment. Brain samples were collected 6 hours after discontinuation of isoflurane, for determination of neurodegenerative biomarkers and cell cycle biomarkers. RESULTS: We found that isoflurane exposure leads to upregulated expression of cell cycle-related biomarkers Cyclin B1, Phospho-CDK1(Thr-161), Phospho-n-myc and downregulated Phospho-CDK1 (Tyr-15). In addition, isoflurane induced increase in Bcl-xL phosphorylation, cytochrome c release, and caspase-3 activation that resulted in neuronal cell death. Systemic administration of CR8 attenuated isoflurane-induced cell cycle activation and neurodegeneration. CONCLUSION: These findings suggest the role of cell cycle activation to be a pathophysiological mechanism for isoflurane-induced apoptotic cell death and that treatment with cell cycle inhibitors may provide a possible therapeutic target for prevention of developmental anesthetic neurotoxicity.

Insulin Reduces Reaction of Follicular Granulosa Cells to FSH Stimulation in Women With Obesity-Related Infertility During IVF.

CONTEXT: Women with obesity usually need larger doses of FSH for ovarian stimulation, resulting in poor outcomes; however, the mechanism is still unclear. OBJECTIVE: To investigate the molecular regulation of FSH receptor (FSHR) expression associated with obesity. DESIGN: Case-control study to improve in vitro fertilization (IVF) outcomes. PATIENTS: Women with obesity (82) and women who were overweight (457) undergoing IVF and 1790 age-matched controls with normal weight from our reproductive medicine center. MAIN OUTCOME MEASURES: FSHR expression was decreased in parallel with body mass index (BMI), whereas the estradiol (E2) level on the human chorionic gonadotropin (hCG) trigger day was significantly lower. RESULTS: FSHR expression in human granulosa cells (hGCs), both mRNA (P = 0.02) and protein (P = 0.001) levels, was decreased in women who were overweight or obese. Both insulin (P < 0.001) and glucose (P = 0.0017) levels were positively correlated with BMI in fasting blood and follicle fluids (FFs) but not with FFs leptin level. We treated human granulosa-like tumor cells (KGN) cells with insulin; E2 production was compromised; the level of phosphorylated (p)-protein kinase B (p-Akt2) decreased, whereas p-glycogen synthase kinase 3 (GSK3) increased; and there were similar changes in hGCs from women with obesity. Stimulated hGCs from women with obesity with compound 21 (CP21), an inhibitor of GSK3ß, resulted in upregulated ß-catenin activation and increased FSHR expression. CP21 also increased the expression of insulin receptor substrate 1 and phosphatidylinositol 3-kinase (PI3K), as well as p-Akt2. CONCLUSIONS: Women with obesity in IVF were associated with reduced FSHR expression and E2 production caused by a dysfunctional insulin pathway. Decreased FSHR expression in hGCs from women with obesity and insulin-treated KGN cells could be rescued by an inhibitor of GSK3ß, which might be a potential target for the improvement of the impaired FSH-stimulation response in women with obesity.

Meta-Analysis of Randomized Controlled Trials Comparing Risk of Major Adverse Cardiac Events and Bleeding in Patients With Prasugrel Versus Clopidogrel.

The use of prasugrel in patients with coronary artery disease (CAD) has been associated with decreased major adverse cardiac events (MACEs) compared with clopidogrel but with an increased risk of bleeding. However, it remains unclear if the risks of bleeding outweigh those of MACEs in patients on prasugrel treatment. We systematically reviewed randomized controlled trials comparing prasugrel with clopidogrel in patients with CAD. We performed a literature search of PubMed, EMBASE, and Cochrane Central Register of Controlled Trial databases from inception to November 25, 2014, and reviewed the reference lists of retrieved articles. A comparative estimate was made for the combined rates of MACEs and bleeding from the same trials in the framework of this meta-analysis and expressed as odds ratios (ORs) and 95% confidence intervals (CIs) in both random- and fixed-effects models. Nine studies involving 25,214 patients were included in our meta-analysis. In both the random- and fixed-effects models, the risks of MACEs outweighed those of major bleeding (OR 7.48, 95% CI 3.75 to 14.94, p <0.0001, random effects) and of minor bleeding (OR 3.77, 95% CI 1.73 to 8.22, p = 0.009, random effects). Results were corroborated in a standard-dose clopidogrel subgroup analysis (OR 7.46, 95% CI 3.54 to 15.68, p <0.0001, and OR 6.44, 95% CI 2.80 to 14.80, p <0.0001, random effects, respectively). In conclusion, despite the increased risk of bleeding associated with prasugrel treatment compared with clopidogrel, the risk of MACEs far outweighed the risk of bleeding.

[Role of CD44 in monocyte transmigration across Cryptococcus neoformans-infected blood-brain barrier in vitro].

OBJECTIVE: To explore the role of CD44 in monocyte adhesion to human brain microvascular endothelial cells (HBMECs) and monocyte migration across an in vitro model of blood-brain barrier (BBB) infected by Cryptococcus neoformans (Cn). METHODS: An in vitro blood-brain barrier model was constructed using a transwell chamber covered with a HBMEC monolayer. The wild-type strain of Cn B4500FO2, TYCC645#32 strain with CPS1 gene deletion and PCIP strain with CPS1 complementation were chosen to infect the monolayer HBMECs. THP-1 cells were added to the upper chamber of transwell, and the relative migration rate was determined by counting the number of the cells entering the lower chambers. The inhibitory effects of anti-CD44 monoclonal antibody and the CD44 inhibitor bikunin were examined on THP-1 binding to and migration across HBMECs. RESULTS: Cn infection of the HBMECs caused markedly enhanced THP-1 cell adhesion and migration across the monolyers (P<0.01) dependent on Cn concentration and exposure time. Addition of anti-CD44 monoclonal antibody and bikunin significantly lowered THP-1 adhesion and migration rates in the BBB model with Cn-infected HBMECs (P<0.01) with a dose dependence of the antibody (within 0-1 µg) and inhibitor (within 0-20 nmol/L). Both THP-1 adhesion rate and migration rate were lowered in the BBB model infected with CPS1 gene-deleted Cn but increased in the model infected with the complemented strain compared with those in the wild-type strain-infected model. CONCLUSION: In the in vitro BBB model, CD44 expressed on HBMECs may play an essential role in monocyte adhesion to and migration across the BBB. The capsular hyaluronic acid may mediate Cn-induced monocyte adhesion and migration.